Preprint The age paradox in post-infectious sequelae: physiological reserve outweighs chronological age in Long COVID susceptibility, 2026, Azhir et al.

[SNT Gatchaman]

The age paradox in post-infectious sequelae: physiological reserve outweighs chronological age in Long COVID susceptibility

Spoiler: Authors

Alaleh Azhir; Jingya Cheng; Jiazi Tian; Ingrid V Bassett; Chirag J Patel; Jeffrey G Klann; Shawn N Murphy; Hossein Estiri

BACKGROUND
Older age is widely considered a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC), typically attributed to immunosenescence and inflammaging. However, whether this association reflects intrinsic biological ageing or accumulated comorbidity burden remains unclear, with implications for clinical risk stratification.

METHODS
We conducted a retrospective cohort study using the Precision PASC Research Cohort (P2RC) from Mass General Brigham, comprising 133,792 COVID-19 patients from 12 hospitals and 20 community health centres in Massachusetts (March 2020-May 2024). PASC was ascertained using a validated computational phenotyping algorithm. We used generalised estimating equations with cluster-robust variance to model PASC risk, causal mediation analysis to decompose age effects through comorbidity burden and acute severity, and specification curve analysis across 768 analytical specifications to assess robustness.

FINDINGS
After adjustment for comorbidity burden, each decade of age was associated with 6% lower odds of PASC (OR 0.94; 95% CI 0.93-0.95). Causal mediation analysis revealed that comorbidities accounted for 145% of the total age effect, indicating inconsistent mediation wherein age's direct protective effect was masked by its indirect harm through chronic disease accumulation. This protection was age-dependent: adults younger than 65 years retained robust resilience independent of comorbidities (ADE: -0.0042, p<0.001), whereas adults 65 years and older showed complete loss of this protection (ADE: +0.0020, p=0.14).

INTERPRETATION
Long COVID susceptibility is driven by physiological reserve rather than chronological age until approximately age 65, beyond which age-related protective mechanisms become exhausted. Risk stratification should prioritise comorbidity burden over birth year in younger adults.

Web | DOI | PDF | Preprint: MedRxiv | Open Access

 

[SNT Gatchaman]

We are accustomed to conceptualising older adults as uniformly more vulnerable to disease sequelae, and indeed they often bear the greatest burden of acute illness. But Long COVID appears to operate differently. What matters is not the years accumulated, but the physiological toll those years have exacted; the accumulated burden of chronic conditions that compromise the body's capacity to resolve infections without lasting consequences. This distinction between chronological age and cumulative physiological burden represents more than semantic refinement; it identifies a modifiable target where none was previously recognised.

However, age-stratified mediation analyses revealed that this protective effect is not uniform across the lifespan. In adults younger than 65 years, the direct protective effect of age remained robust (ADE: −0.0042, p<0.001), with comorbidity burden accounting for 152% of the total effect through inconsistent mediation.

In adults 65 years and older, this pattern fundamentally changed: the direct protective effect of age disappeared entirely (ADE: +0.0020, p=0.14), with comorbidity and severity together fully mediating the age-PASC relationship (81% and 26%, respectively). This threshold effect suggests that the physiological mechanisms that confer resilience to Long COVID in younger adults, whether immunological, metabolic, or related to tissue repair capacity, become exhausted or overwhelmed beyond the age of 65. The clinical implication is that risk stratification strategies may need to operate differently across this divide: in younger adults, comorbidity burden should drive clinical concern regardless of age, whereas in older adults, chronological age itself regains prognostic relevance as a marker of diminished reserve.

An alternative, more troubling possibility is that PASC itself induces durable changes in immune function or tissue integrity that increase vulnerability to future episodes. Under this model, each PASC episode would compound risk for subsequent occurrences, suggesting a form of immunological scarring with cumulative consequences. This interpretation is supported by evidence that SARS-CoV-2 reinfection increases the cumulative risk of death, hospitalisation, and sequelae in multiple organ systems, with the hazard ratio for at least one sequela increasing from 1.35 after first infection to 2.11 after second infection and 3.00 after three or more infections. While our observational design cannot adjudicate between these mechanisms, the finding underscores that PASC should not be conceptualised as a self-limited condition; for a substantial subset of patients, it may represent the beginning of a chronic, potentially progressive disease trajectory.